Production of secondary amines from nitrogen compounds



Patented Nov. 6, 1 945 PRODUCTION OF SECONDARY AMINES FROM NITROGEN COMPOUNDS William S. Emerson, Dayton", Ohio no Drawing. Original appllcationDeoember is,

1940, Serial No.

Divided and this application September 15, 1944, Serial No. 554,329

, 8 Claims.

The present invention relates to the reductive alkylation 'of amines, nitro, nitroso and azo com-' pounds by means of aldehyds or ketones and hydrogen gas in the presence of a hydrogenation catalyst. The invention relates particularly to alkylation in the nitrogen-containing radical of the amino, nitro, nitroso or azo compound to produce N-alkyl or N-aralkyl substituted amines. The invention also relates to methods of controlling the proportion of secondary and tertiary amines produced in such reactions and is specifically directed to the production of secondary and tertiary amines.

The principal objects of the present invention are to provide a simple and economical method.

of obtaining N-alkylated or N-aralkylated amines by-the reduction with hydrogen of an aldehyde or a ketone and an amine, nitro, nitroso, or azo compound or an intermediate condensation product of the specified carbonyl compounds and one of the nitrogen compounds. Another object of the invention is to provide a method of such reductive alkylation of nitrogen compounds whereby the yield of secondary N-monoaikylated or tertiary N-dialkylated amines may be controlled to the extent of suppressing or entirely eliminating the formation of the undesired alkylated amines. Other objects and advantages of the invention, some of which are specifically referred to hereinafter, will be apparent to those skilled in the art. a

This application is a division of my copending application 8. N. 370,355, filed December 16, 1940. In my application 8. N. 332,975, filed May2, 1940, now issued as U. S. Pat. 2,298,284, of which my copending application 8. N. 370,355, filed December 16, 1940, is a continuation-in-part, I have disclosed that by reducing a mixture'of an aldehyde and a nitro or amino compound with hydrogen in the presence of a platinum or Raney nickel reduction catalyst under neutral or slightly a1- 'kaline reaction conditions, secondary amines are formed while the simultaneous formation of tertiary amines is suppressed or entirely avoided. Such neutral or slightly basic or alkaline conditions are obtained by placing in the reaction mixture undergoing hydrogenation an alkali-metal salt or a weak organic acid such 'as sodium ace-- tate,sodium carbonate, sodium stearate or the like. I have also shown in my'copending application and in my application 8. N. 332,975, that if acid oonditions'are maintained in a similar reaction mixture, for example, by the presence of trimethylamine hydrochloride in the reaction.

mixture, tertiary amine'sare formed to the exclusion or suppression of secondary amines.

I have discovered that in such reductive allrylations with nitrogen compounds and carbonyl compounds, that neutral or slightly basic reaction conditions maintained by the addition of sodium acetate or other alkali-metal salts of weak organic acids favor the formation of sec-. ondaryamines while acid conditions maintained by the addition oi trimethylamine hydrochloride, acetic acid or the like, favor the formation of tertiary amines.

Although I refer to neutral or basic and acid conditions or media throughout this specification, it is not to be understood that acidity or alkalinity in and of itself is directly responsible for the improvements specified. Sodium acetate, acetic acid or trimethylamine hydrochloride do change the pH or hydrogen-ion concentration of the reaction mixture, but they probably act by virtue of their ability to favor certain condensation reactions or the like rather than as a result 'of their acidity. Sodium hydroxide, for example, which produces alkaline media, hinders reaction. Hence it is to be understood that when acid or basic media or conditions are referred to, these terms are used merely for convenience to classify the various kinds of condensing agents which are added to the reaction mixture.

When the carbonyl compound used in such reactionais a ketone instead of an aldehyde, some- I what more drastic reaction conditions, such as higher temperatures, are necessary to produce secondary amines in neutral or slightly basic media. Ketones do not yield tertiary amines in neutral or slightly basic media. In acid media,

on the other hand, ketones yield secondary instead of tertiary amines, even under drastic reaction conditions such as elevated temperatures of reaction and concentrated acid.

I have also discovered that besides amines and nitro compounds, other nitrogen compounds such as nitroso and azo compounds, for example, nitrosobenzene and azobenzene, may be used in the reactions. Furthermore, I have found that substituents such as hydroxyl and amino radicals in the nitrogen compound have an activating eflect on the reaction. Thus, when an aromatic nitrogen compound contains an amino or a hydroxyl group ortho, or particularly, para, to the nitro, amino, nitroso or azo group, the reductive alkylation of such substituted compound with. ketones progresses more rapidly to the formation of secondary amines while with aldehydes, reaction is also accelerated and tertiary amines are formed tic reaction conditions.

in either basic or acid media. Alkyl groups substituted in the benzene ring also have a mild activating influence which is less pronounced than thatof amino or hydroxyl groups, however. In the case of azo compounds, hydroxy or dimethylamine groups, either ortho or para to the azo group, have an activating influence and tertiary amines are formed in alkaline or acid media.

The methods of adopting the present discovcries and those of my copending application, S. N. 370,355, and my application, S. N. 332,975, to the production of secondary ortertiary amines by reductive alkylation are set forth in the examples which follow hereinafter, but may be briefly summarized as follows:

hydroxyl groups in the ortho or para position, together with an aldehyde, in an alkaline medium (activating substituents favor the formation of tertiary amines),

2. A nitrogen compound containing activating substituents together with a ketone in an acid medium, or less favorably, in an alkaline medium, or

3. An unsubstituted nitrogen compound or a nitrogen compound free from activating substituents, as in 1, together with a ketone in an acid medium or in an alkaline medium under more drastic reaction conditions.

B. Tertiary amines may be made by the reaction of hydrogen in the presence of a hydrogenation catalyst on a reaction mixture comprising:

1. A nitrogen compound (nitro, amino, nitroso or azo compound), with or without activating substituents, together with an aldehyde in acid media, or

2. A secondary amine together with an aldehyde in an acid medium.

Ketones are inactive or are'not as reactive as aldehydes in the formation of tertiary amines, either in acid or alkaline media, even under dras- They may be advantageously used, however, in the production of secondary amines in accordance with the processes summarized above, especially when used in an acid instead of an alkaline medium. The reaction of primary aromatic amines with aldehydes, particularly formaldehyde, in acid media, is complicated by the formation of tarry condensation products of the type of anhydroformaldehydeaniline and the like and hence, to avoid such formation of condensation products, resort should be made to primary aromatic nitro compounds or the like as starting materials; such condensation products do not readily formbetweenprimary aromatic amines and ketones or secondary aromatic amines and either aldehydes or ketones and hence reaction mixtures containing these compounds may be used. When formaldehyde is used in any reaction mixture under acid conditions complications are also likely to result from polymerization of the formaldehyde. These complications do not result with acetalacid reaction mixtures contemplated by the present invention, however. The reductive alkylation. product of formaldehyde and primary aromatic amines, furthermore, is a tertiary amine, in many cases, even in alkaline reaction media.

The yields in the foregoing alternative processes for the production of secondary or tertiary amines vary somewhat and hence one will be preferable to another. The processes also differ in the proportion of secondary or tertiary amines which are formed. By using ketones to prepare secondary amines, for example, it is possible to operate in such a manner that no substantial proportion of tertiary amine is formed as a byproduct, which may be highly desirable, whereas in a reaction where the tertiary amine is the desired product it may bemore economical to adopt an alternative which gives a high yield of tertiary amine that may be contaminated with small proportions of secondary amines in'preference to one which gives a small yield of tertiary amine uncontaminated with secondary amines, since secondary amines can be converted in a separate subsequent step to tertiary amines.

It is known that secondary. and tertiary amines have been prepared by reductive alkylation by the use of nascent hydrogen generated in situ from the reaction of a metal and an acid or by the use of hydrogen gas in the presence of a nickel catalyst at high temperatures to 200 C.) and under high pressures (50 to 150 atmospheres). That such reactions could be conducted with hydrogen gas in the presence of a hydrogenation catalyst under relatively mild reaction conditions (room temperature and pressures of about 2 to 4 atmospheres) by the use of the specified acids or salts which modify the acidity (pH or hydrogen-ion concentration) of the reaction medium and serve as condensing agents or modify the reaction in some other manner, was unexpected. 15y means of the processes of the invention it I has been possible to prepare in an advantageous manner amines which have not been heretofore prepared or which could not be prepared by heretofore known methods. Since the methods disclosed herein show how alkylation may be stopped at the formation of the secondary amine the methods are useful for the preparation of tertiary amines having two different alkyl substituents on-the amino nitrogen atom in an advantageous manner. 7

In the examples whichfollow, typical methods of practicing the processes of my invention are set forth: Example I.-N-ethylaniline using acetaldehyde and alkaline conditions Into an apparatus for catalytic reduction, preferably provided with a stirrer or means for shaking, are placed 93 grams (about 1 mol) of aniline dissolved in 1500 cc. of 95% ethyl alcohol and about 88 grams (about 2 mols) of acetaldehyde, 10 to ,20 grams of fused sodium acetate, and

about 30 grams of Raney. nickel catalyst, which dehyde orhigh r ald y when d in th 76 talned at room temperature and the hydrogen I naphthylamine for 1 C. for the the aniline used.

E's-ample IL-N-n-heptfllaniline using heptalde- .hyde and alkaline conditions By proceeding as in Example I, using from 2 to 5 mols of heptaldehyde instead of acetaldehyde and iractionating the product in vacuum,

N-n-heptylaniline is obtained.

N-n-heptylaniline has a boiling point of 125 to 130 C. at a pressure of 30 mint," a specific gravity of 0.906 at 20/20 C. and a refractive index at 20 C. 01' 1.5080 for the sodium D line.

Izample III.--N-n-butul-alpha naphthulmnine using butyraldehvde and alkaline conditions By proceeding as in Example I but substitutin: butyraldehyde for acetaldehyde and alphaaniline in'molecular proportions, and fractionating the product in vacuum, N-n-butyl-alpha-naphthylamine is obtained in 80% of the theoretical yield.

The new compound, N-n-butyl-aipha-naphthylamine, has a. boiling point of 155 to 167 C.

1 at a pressure of 8 mm., a specific gravity of 1.004

at 20/20 and a refractive index of 1.5963 at 20 sodium D line. Its hydrochloride melts at 151 to 152 C.

Example IV.--N-ethvl-p-anisidine using acetatdehude and alkaline conditions By proceeding as in Example l but substituting p-anisidine for aniline in molecular proportions and fractionatingthe product, N-ethyl-panisidine is obtained in 51 yield.

N-ethyl-p-anisidine has a boiling point of 135 to 140 C. at a pressure of. 20 mm, a specific iiravity of 1.017 at 20/20 and a refractive index of 1.5444 at 20 C. for the sodium D line. Its pera-bromobenaenesulfonamide melts at 113 to 1 4 C.

slightly alkaline about 1000 cc. of water and C. at 25 mm., consisting of 3 applied to the autoclave and the mixture is maind at room temperature. After about 4 mois of hydrogen have been absorbed, the reduction is stopped and the catalyst is removed by filtration or decantation. The filtrate is made slightly acid with hydrochloric is distilled oil. The residue is then diluted with made slightly alkaline with sodium hydroxide. It may be subsequently extracted with ether and the extracts combined and alter evaporation or the ether, fractionally distilled. However, theoriginal residue without dilution with water may be made basic and then subjected to vacuum distillation. The product, N-n-butyianiline, is obtained in a yield of about 77% to 81% of the theoretical and has a boiling point of 235 to 245 C.

Emmple VIL-N-di-n-but1!l-p-iaminophenol from p-nitrophe'nol and buti/raldehyde under alkaline conditions When p-nitrophenol issuhstituted in Esample VI for nitrobenzene and hutyraldchyde is present in excess, the product obtained is substantially all N-di-n-butyl-p-aminophenol. It is 'dimcult to get any yield of secondary amine in this reaction because of the presence of the activatinu hydroxyl group in the para position Example VlIl.-'-p-chloro-n-buwlaniline from pchloronitrobeneene and hutyraldehualc under alkaline conditions By substituting p-chloronitrobenzenc for nitrobenzene in molecular proportions in ample W. the product obtained consists of unalwlated pchloroaniline, a fraction boiling at 105 to M5 n-hutylaniiine and p-chloro-n-butylaniline, and higher ho fractions in which occurs p-chloro-n-butylaniline.

The yield in this case hidicatcs that chlorinesubstituents have no activating influence since the yield is substantially identical with that oh- I tained when nitrobcnzene is reacted under the same conditions. The lack of activating u---.

ence of the chlorine is shown more than any thing else by the presence of lkylated pchloroaniline in the reaction mixture.

' Example IX.-N-di-n-hepiyl-p-toluidine frown-p- Example V.-N-n-butyl-p-anisidine asino buturaldehyde and alkaline conditions By substituting butyraidehyde for acetaldehyde in molecular proportions in Example IV and proeeding as therein described, N-n-butyl-p-anisidine is obtained in 65% yield.

This new. compound, N-n-butyl-p-anisidine, has a boiling point of 142 to 145 C. at a pressure of 6 'mm., a specific gravity of 0.983 at 20/20 and a refractive index of 1.5207- at 20 C. for the sodium D line. Its

to 188 C. v

Example VL-N-n-bntylaniline from nitrobenzne and butm'aldehyde under alkaline conditions hydrochloride melts at 187.5

linto an autoclave Drovided'with r stirrer are placed123 grams (about 111101) of freshly distilled nitrobenzene, 20 grams of fused sodium acetate, 1500 cc. 0! 96% ethyl alcohol, 94 grams (about 1.8 mol) of freshly distilled n-butyraldehyde and 30 grams of ,Raney nickel catalyst.

The autoclave is evacuated and thereafter an initial. pressure 01 3 atmospheres of hydrogen is a are obtained, the latter in a refractive index of 1.5039 at 20 Dline. Its hydrochloride melts conditions By substituting heptaldehyde for hutyraldehyde and p-nitrotoluene for nitrobenzcnc in molecular proportions in Example V1 and proceeding as therein otherwise described, N-mono-nheptyl-p-toluidine and N-di-n-hcptyl-p-toluidine yield of 34% of the theoretical. The latter compound, N-di-n-heptyl-p-toluidine, is a. new compound and has a boiling point of to-200 C. at a pressure of 2.5 mm., a specific gravity of 0.043 at 20/20 and a C. for the sodium at 136 C. The has a mild acti nitrotolucne and heptaldehmle under alkaline methyl group of the nitrotoluene vating influence, the formation of both secondary and tertiary amines being a result thereof.-

Earample X.--N-ethylaniline urine acetaldehyde, alkaline conditions and platinum catalyst By substituting 2 grams of a platinum oxide catalyst prepared according to the method of Adams, Voorhees and Shriner (Organic 8yn-.

theses," coll. vol I, 1932, page 452) I for the Raney nickel catalyst and. proceeding otherwise as in,

acid and the alcohol (0.1 moi) oi nitrobensene, V of butyraldehyde and 10 cc. of glacial acetic acid 01 41% 01 the theoretical.

Example XI. N -benzyl-alpha-naphthulamine using benzaldehude and alkaline conditions 2,see,eoe

' Example 1, N-ethylaniline is obtained in a yield its picrate, which had a melting point of 123 to 125 C. The melting point of the picrate is given as 125 C. by Reilly and Hickinbottom, J. Chem. Soc. of London, 1918, vol. 113, page 99.

Example XIIL-N-n-dz-n-butulamline usino ni- By substituting benzaldehyde for acetaldehyde and alpha-naphthylamine tor aniline in molectrobenzene and conditions uiar proportions in Example I and proceeding as By using 3 grams of Raney nickel catalyst inotherwise therein indicated, benzylalpha-naphstead of the platinum catalyst in Example XII thylamine is obtained. Its benzamide has a and2 grams of'trimethylamine hydrochloride inmelting point of 103 to 104 C. stead of the acetic acid, and using 36.9-grams Table L-Reductive allculation of nitrobenzene 9' mol) of mtmbenzene so that,the ratio of with but mldehyde in media of Dummy acid nitrobenzene to butyraldehyde is 1.1, a yield of ties I 63% N-di-n-butylaniline is obtained. (Theyield is 98% based on the aldehyde consumed.)

The efiect of various of the added agents and The use of larger ratios at aldehyde in this acidity engendered by their use, as well as the preparation results in lower yields 01 the tertiary influence of other factors, is illustrated in the amine. following results. In these tests, the specified Y quantity of butyraldehyde was reacted with 0.10 g zzg i gz ggi zx z zgggfi 22: 2,? mol of nitrobenzene in the presence of 3 grams of Raney nickel catalyst. The pH represents the- Adopting the method of Example XII, using acidity of the reaction mixture as observed on glacial acetic acid to provide the acid medium a Hellige pH meter. The yields are expressed and platinum catalyst and substituting the anas per cent of secondary (N-n-butylaniline) and 25 propriate aldehyde and nitro compound, the foltertiary amines (N-di-n-butylaniline) respeclowing yields of the respective aliphatic and arotively. matic tertiary amines were obtained. (Melting Mols Mols Per cent yield I hydrobutyr- Run an h d Solvent Condensing agent pH s i hid pi-gse nt gga T563112? I 0.50 0.30 Alcohol... 2g.sodium acetate... 8.81 0.42 0.10 "fi 8.81 0.42 0.12 "I 8.81 0.39 0.13 r0 8.81 0.46 0.13 do .-c.0 8.81 0.40 0.13 Dioxane... ...-.c.o 7.41 0.41 0.13 Alcohol... 2g.trimethylsminehydrochlorlde.. 4. 73 0.42 0.13 -.-do 2g.sodiumformete 8.44 0.41 0.13 .-.do 2g. sodium carbonate 0.22 0.43 0.13 ...do 6cc.40%trimethylamine... 0.05

Example XXL-N-di-n-hutylaniline using mimbenzene, acts. conditions and platinum catalyst Into the pressure bottle of a machine for catalytic reduction is placed a solution of 12.3 grams 21.6 grams (0.3 mol) in 150 cc. of 95% ethyl alcohol. To this solution was then vadded 0.1 gram of platinum oxide catalyst prepared according to the method of Adams,

Voorhees and Shriner ("Organic Syntheses, collective volume I, 1932, page 452) and the mixture was shaken on the machine for 96 hours during which time 0.66 mol of hydrogen was absorbed. After this hydrogenation the mixture was acidiiied with 17 cc. of dilute hydrochloric acid and the platinum catalyst was removed by filtration. The alcohol was evaporated from the filtrate, the

points of derivatives used for identification pur- I poses are listed in last column.)

Derivative and M. P. Yield thereoi Percent l N-diethyieniline 77 Picrate, 130-140" C. 2 N-di-n-propylaniiine.- 34 Methiodide, 153-1136 C. 3 N-ilillelthyii-naipha-naph- 40 Picratc, 162-154 0.

t am e. 4 N-dY-n-butylmethyh} 50 Hydrochloride, 131.0-13l.5

amine. o

Picrate,00.007.6 O. 6 N-digthylmethyi- 92 Pierate, 183-185" 0.

am e. B N-dl-n-propylmethyl- 45 Picrete, 0243 0.

amine.

The properties of the respective amines thus prepared were as follows:

Specific Refractive Boilinz range grav ty n or i N-di-n-bu lmethylemine.. MSG-103C 0.782 1.4302

0 N-dinro gylmethylamine- 1l0-122C 0.743 1.4076

8 N-dlet yl-elphe-nephthyllot-165 0.130 mm-.... 1.016 1.5961

amine.

to a yield 01' 11%, based on the nitrobenaene.

The product was further identified by means 0!:

obtained, which corresponds Example XV.--N-iaopropulanilinc using acetone and acid conditions Substituting acetone for the acetaldehyde used in Example XII in equimolecular amount and proceeding as otherwise therein described, a secondary amine, N-isopropyianiline, instead of a tertiary amine, was obtained in 54% yield. The

. aseaeoe' N-isopropylanillne had a boiling range 01' a to heptylaniline was obtained in 74% yield and was 207' C. and formed a benzamide derivative havidentified as the p-bromobenzenesultonamide ing a melting point of 63 to 65 0. having a melting point oi, 114 to 115 0.

Example XVI.--N-is 9r i i!lmethfllamine using acetone andacidconditions Acetone and nitromethane when reacted according to the procedure of Example XII, produced N-isopropylmethylamine in 59% yield.

The product had a'boiling range of 45 to 55 C.

and was identified as a point 01' 183' to 135 C.

Example XVII-N-benzhl-N-n-Mtvlanilifle aiina N-benznlphenulhydrozylamine and acid conditions By using butyraldehyde and N-benzylaniline in .the molecular ratio or 2:1 and hydroxenating in accordance with the procedure described in Example XlI, N-benzyl-N-n-butylaniline was obgo tained in 3% yield, 84% or the N-benzylaniline being recovered unchanged.

A larger and more satisfactory yield (38%) oi N-benzyl-N-n-butylaniline can be obtained by reacting butyraldehyde and N-benzylphenylhydroxylamine (which can be prepared by the method of Vavon and Craicinovic, Compt. rend, 1228, vol. 187, page 420) in the molecular ratio of 2:1 according to the procedure of Example XII, using platinum catalyst and acetic acid in the reaction mixture.

N-benzyl-N-n butylaniline distills at 175 to 182 C. at a pressure oi. 10 mm., and has a specific gravity (/20 C.) of 1.019 and a refractive index 01' 1.5810 at 20 C. for the sodium D line. Its picrate had a melting point of 126 to 128 C.

By using sodium acetate instead of acetic acid and Raney nickel catalyst instead ot a platinum catalyst, as in Example I, N-benzylphenylhydroxylamine and butyraldehyde in the molecular ratio of 1:2 produced N-benzylaniline in 54% yield without the formation of any quantity of the tertiary amine,

that could be isolated.

Example XVIIL-N-n-bniylaniline using aaobenzene and alkaline medium Into a machine for catalytic reduction was placed a solution of 18.2 grams (0.1 mol) of ambenzene, 18.0 grams (0.25 mol) of butyraldehyde and 2 grams of fused sodium acetate dissolved in.

catalyst was removed by filtration, the filtrate was on acidified with hydrochloric acid and the alcohol was evaporated. The product was recovered by making the residue alkaline, extracting the alkaline residue with ether, drying the ether extract over sodium hydroxide and subsequently distilas lating the extract.

The yield of N-n-butylaniline a secondary amine, was 71% and the product was identified as the p-bromobenzenesuli'onamide which had a melting point or 85 to 86 C.

1 Example XIX.N-n-heptulanil ine using carbonacne and alkaline medium Substituting an equivalent amount of heptaldehyde for the b'utyraldehyde 01' Example XVIII and proceeding as therein otherwise indicated. N41- In the case or higher molecular weight amines, such as N-n-heptylaniline, the reaction mixture after hydrogenation need not be acidified before evaporation of the solvent (alcohol).

- Example XX.N- benzulanilinle using azobenzene 10 picrate having a melting N-benzyl-N-n-butylaniline,

and alkaline conditions By the procedure of Example XVIII, substituting benzaldehyde in an equivalent amount for the butyraldehyde, N-benzylaniline was obtained in 49% yield. The product, N-benzylaniline, was identified as the hydrochloride, having a melting point of 210 to 2120.

azobe-nzene and alkaline conditions Substituting N-dimethyl-p-aminoazobenzene in an equivalent amount for azobenzene and proceeding as otherwise. specified in Example XVIII, the products, N-dimethyl-N'edi-n-butyl-pphenylenediamine in 76% yield and N-n-butylaniline in 73% yield were obtained. The picrate of N-dimethyl-N-di-n-butyl-p-phenylenediamine has a melting point of 121 to 122 C. i

The presence of the amino (or alkyl or dialkylamino) group para to the one group has anactivating influence and instead of getting solely a secondary amine, as would be obtained under alkaline conditions with an unsubstituted azo compound, a tertiary amine is obtained. The activat- Jng influence of a hydroxy group is shown in the two next examples (m and ll r a a m p z e XXIl.-N-di-n-bntyl-p-aminophenol using p-hzldmryazobenzienc and alkaline conditions Substituting an equivalent amount or p-hydroxyazobenzene for the azobenaene in Example l and proceeding as therein otherwise indicated, the tertiary amine, N-di-n-butyl-p-aminos phenol, was obtained in 46% yield. The product so after recrystallization from acetic was isolated as the benzoate by treating the reaction mixture with benroyl chloride and aqueous alkali. i

The benaoate of N-di-n-butyl-p-aminophenol, acid, has a melting point of 232 to 233 C.

Ewample XXIl'l.-ll (N di n blitz/lamina) -2- naphthol using 1 -pllenylazo-2-naphthol and alkallne conditi ns Utilizing the procedure of Example xvm, by substituting l-phenylazoa naphthol for azqbenzene in equivalent amount, the tertiary amine l-(N-dien-butylaniinol -2-naphtho1 was obtained in 41% yield. The product was isolated by addpreponderance of tertiary amines. Example XXIVP-N-n-butulaniline using nitrosobenzene, and alkaline conditions Utilizing the foregoing procedures, N-n-butylaniline was obtained in 45% yield by the reductive alkylation of nitrosobenzene (0.1 mol) and butyraldehydes,

butyraldehyde (0.1 mol) in the presence of Raney nickel catalyst grams) and sodium acetate (2 grams), Aniline is also recoverable from the reaction mixture.

Emample XXV.N-benzyloniline using nitrosobenzene and alkaline conditions Using the foregoing procedures, N-benzylaniline was obtained in 35% yield by the reductive alkylation of nitrosobenzene (0.1 mol) and benzaldehyde (0.1 mol) in the presence of Raney nickel catalyst (5 grams) and sodium acetate (2 rams). From the reaction mixture some aniline is also recoverable.

In the two foregoing examples (XXIV and XXV) the use of nitrosobenzene in the reductive alkylation required larger quantities of catalyst than would be required for the corresponding reduction of nitro or amino compounds and the yields of secondary amines is lower and the product is contaminated with tars. The preparation of secondary amines from aromatic nitroso compounds requires a greater degree of control of the reaction than nitro or amino compounds.

The processes of the invention are applicable to the reductive alkylation of various nitrogen compounds, including aliphatic and aromatic amines such as methylamine, ethylamine, propylamines, butylamines, amylamines, aniline, p-toluidine, p-anisidine, alpha-naphthylamine, beta-naphthylamine, phenylpropylamines (phenylaminopropanes) and the like; aliphatic and aromatic nitro compounds such as nitromethane, nitroethane, nitropropanes, nitrobutanes, nitropentanes, nitrobenzenes, nitrotoluenes, nitrophenols, nitroanisoles, chlorinated nitrobenzenes, nitronaphthalenes, nitronaphthols, nitronaphthylamines, phenylnitropropanes and the like; aromatic nitrosoamines such as nitrosobenzene and the like; and azo compounds such as azobenzene and substituted azobenzenes such as N-dimethylp aminoazobenzene, p hydroxyazobenzene, 1- p eny1azo- -naphthol and the like. i The nitrogen compounds may contain chlorine, alkoxy or aryloxy substituents, for example, chloroaminobenzenes, nitroanisoles, nitrodiphenyloxides and the like, which substituents have no substantial activating influence. However, when amino, hy-

droxy or alkyl substituents are present, as previously mentioned, the compound is activated as a result thereof.

In the-preparation of tertiary amines, N-monoalkylated secondary amines may be used as starting materials, as is obvious, especially when a tertiary amine with two different substituents on the amino nitrogen atom is the desired product. As heretofore mentioned, the presence of activating groups in the nitrogen compounds particularly hydroxy, amino, and substituted amino groups, and particularly those para or ortho to the reacting nitrogen-containing radical, influence the degree of alkylation effected and the ease of the reaction.

Carbonyl compounds which may be used in the reaction include both aliphatic as well as are-- Aldehydes are matic aldehydes and ketones. more reactive tha ketones, as heretofore mentioned, and ketones in most cases cannot be used to effect alkylation beyond the formation of secondary amines. Examples of aldehydes and ketones which may be used in the processes are formaldehyde, acetaldehyde, propionaldehyde, pentaldehydes, hexaldehydes, heptaldehydes, benzaldehyde, acetone, ethyl methyl ketone, diethyl ketone, acetophenone, pronitrogen compound taking piophenone'and methyl phenyl diketone and the like. Generally branched-chain or arboraceous aldehydes and ketones do not react as readily as straight-chain compounds.- Formaldehyde, as heretofore mentioned, may lead to complications.

Although I have referred to alkylation throughout this specification, it is to be understood that the term when used in the broad sense includes the introduction of aralkyl groups such as is effected by the use of benzaldehyde and the like, as well as alkyl groups. The process of the invention, however, finds its greatest applicability in the case of aliphatic aldehydes whose use in such reactions has not heretofore been possible in a facile mannen Although I have particularly referred to reaction mixtures containing carbonyl compounds and nitrogen compounds as starting materials, condensation products of the two, or intermediate products of their reductive alkylation may be used.

As hydrogenation catalysts for the reduction, Raney nickel catalysts, platinum black, palladium black and platinum oxide and similar low-pressure hydrogenation catalysts are preferred. Catalysts such as copper chromite are not operative at the low temperatures and pressures contemplated by the present processes. When using acid conditions of reaction, platinum oxide catalysts are preferred to Raney nickel catalysts. With respect to choice of catalyst, it is also to be noted that certain hydrogenation catalysts are more sensitive to chlorine and sulfur compounds than others and hence it the compounds involved in any particular reaction contain halogen or sulfur substituents, proper selection of a catalyst to avoid complications should be made. The pro portion of catalyst used for the reaction may be varied over a wide range, as illustrated in certain of the examples.

The alkaline conditions referred to in this specification may be obtained by the use of sodium acetate, sodium propionate, sodium butyrate, sodium stearate, sodium carbonate, and in general, other alkali-metal salts of weak organic acids, as disclosed in my co-pending application Serial No. 7 .355 and my application Serial No. 332,975. Sodium hydroxide gives a lower yield of product than sodium acetate and in some cases completely suppresses alkylation, hence is to be avoided. Generally 10 grams to 20 or more grams of fused sodium acetate should be used for each mol of part in the reaction and the yields are not materially changed by the presence of greater proportions. Fused sodium acetate is preferred but it is not essential that the salts used should be anhydrous.

Acid conditions referred to in this specification may be obtained by the use of acetic acid and other weak organic acids, trimethylamine hydrochloride and similar salts of strong (mineral) acids and weak organic bases, containing no alkylatable hydrogen atoms attached to the nitrogen atom, preferably salts of tertiary amines. Mineral acids such as hydrochloric acid and the like cannot be used advantageously. Approximately 30 to 100 grams of glacial acetic acid, for example, to each mol of reacting nitrogen compound should be used.

The reactions may be carried out in various solvents. The examples illustrate the use of ethyl alcohol and dioxane as a solvent but ethyl acetate, methyl alcohol, propyl ether and the like may be used. The essential requisite of the solvent is that it be nert isopropyl alcohol, isoand an aldehyde (RCHO ON-CRIB --e tn I aa ac a erally the carbonyl compound should be in excess of that required by the particular reaction which it is desired to eii'ect.

The temperatureswhich may be used in the reactions vary from normal room temperatures to approximately 100 0., although the preferred range is about to 40 C. Generally the reac- Inasmuch as the ioregoing description comprises preferred embodiments oi the invention, it is to be understood that my invention is not to be limited thereto and that modifications and variations may be made therein to adapt the invention. to other speciiic uses without departing substantially from its spirit or scope as denned in the appended claims.

I claim: 1. The process of producing an N-alkylated amine'co'mprising the hydrogenation of a mix- .ture of two compounds, one or which is an ortion will proceed without the addition of extraneous heat and with large batches cooling may be desirable to control the reaction. Likewise, the

pressures may bevvaried greatly, for example,

from normal atmospheric pressure to 10 or more atmospheres. Preferred pressure conditions, how

ever, are from 2 to 4 atmospheres.

By interrupting-the reductive alkylation-or arcmatic nitrocompounds with aliphatic or aromatic aldehydes according to the present invention at an intermediate stage it is possible to isolate substantial amounts of hydroxylamines. The media may be either acid or-alkalinej as herein described. These hydroxylamines can be rearranged with acids such as sulfuric acid to give the correspond ing aminophenols. Hence, by this procedure I am able to produce substituted hydroxylaminesand aminophenols in an advantageous manner. Furthermore, these intermediate products indicate the probable mechanism of reductive alkylation processes according to the invention. Briefly the reactions may be typified by that of nitrobenzene which m y be represented as follows:

Hr RCHO Q Hr NCH|R N-benzylphenylhydroxylamine prepared by interrupting the reductive alkylation oi nitrobenzene with benzaldehyde, condenses with n-butyraldehyde in an acid medium to give N-benzyl- N-n-butylaniline. The yield is 38% when 2 mols of butyraldehyde are present to each mol of henzylphenylhydroxylamine. (Example XVII.)

As used herein and in the claims the term weak organic acid" is to be understood to silnli'y. monocarboxylic aliphatic acids such as acetic acid, formic acid, propidnic. acid, butyric' acid, dicarboxylic and polycarboxylic acids and the like and to distinguish from strong organic acids such as benaenesulronic acids and similar noncarboxylic acids and mineral acids.

ganic nitrogen compound selected, from the group consisting 01' primary and secondary aliphatic and aromatic amines, aliphatic and aromatic nitro compounds and aromatic nitroso and azo compounds, and the other of which is a ketone, in the presence oi a hydrogenation catalyst and a condensing agent consisting oi a weak or-.

ganic acid.

2. In the method of producing an N-alkylated organic compound by the hydrogenation in the presence of a hydrogenation. catalyst of a mixture 01' two compounds, one 01' which isan organic nitrogen compound free from hydroxyl and 1 amino substituents and selected from the group consisting of primary and secondary aliphatic and aromatic amines, aliphatic and'aromatic nitro compounds and aromatic nitroso and azo compounds, and the other of which is a ketone.

I the improvement comprising conducting the hydrogenation -in the presence of a condensing agent consisting of a weak organic acid at a temperature within the range of approximately 15 to C. and at a pressure 01 approximately 1 to4 atmospheres. 3. The process as defined in claim 1 in which the condensing agent is acetic acid.

4. The process as deilned in claim 1 in which 0 the hydrogenation catalyst is 01' the Raney nickel type.

5. The process of producing N-isopropylani-' line comprising the hydrogenation of a mixture or acetone and nitrobenzene in the presenceo! a hydrogenation catalyst and acetic acid at a temperature within the range or approximately 15 to 100' O. and at a pressure of approximately 1- to 4 atmospheres.

6. The process oi producing an N-isopropylated aromatic amine comprising the hydrogenation 0! a mixture oi an aromatic nitro-compound and acetone in the presence or a hydrogenation catalyst and a condensing agent consisting of acetic acid.

7. The process at producing an N-alkylated aromatic amine comprising the hydrogenation of a mixture of an aromatic nitro compound and an aliphatic ketone in the presence of a hydrogenation catalyst and a condensing agent consisting oi a weak organic acid.

. 8. The process asdeiincd in claim 7 and further characterised in that the condensing agent is acetic, acid. a

,wnmu s. s. 

